world cancer report - iarc

several carcinomas (e.g. breast, head and
neck, oesophageal and lung cancers).
There is also limited evidence for transcriptional
activation of cyclin A (an S-
TELOMERES
AND TELOMERASE
The ends of eukaryotic chromosomes are
referred to as telomeres. These contain
many copies of a repetitive DNA
sequence, which in vertebrates is the
hexanucleotide TTAGGG. The telomeres of
normal human somatic cells shorten by
50 to 150 base pairs every time cell division
occurs. This appears to act as a cell
division counting mechanism: when a
cell's telomeres have shortened below a
critical length, the cell exits permanently
from the cell cycle. Normal cells thus
have a limited proliferative capacity, and
this acts as a major barrier against carcinogenesis.
Cells that have accumulated
some carcinogenic changes are unable to
form clinically significant cancers unless
this proliferation barrier is breached.
More than 85% of all cancers achieve this
by expressing an enzyme, telomerase,
that synthesizes new telomeric DNA to
replace the sequences lost during cell
division (Shay JW, Bacchetti S, Eur J
Cancer, 33A: 787-791, 1997).
REFERENCES
1. Hunt T (1989) Maturation promoting factor, cyclin and
the control of M-phase. Curr Opin Cell Biol, 1: 268-274.
2. Pines J (1995) Cyclins and cyclin-dependent kinases: a
biochemical view. Biochem J, 308 (Pt 3): 697-711.
3. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive
and negative regulators of G1-phase progression. Genes
Dev, 13: 1501-1512.
4. Weinberg RA (1995) The retinoblastoma protein and
cell cycle control. Cell, 81: 323-330.
5. Hartwell LH, Weinert TA (1989) Checkpoints: controls
that ensure the order of cell cycle events. Science, 246:
629-634.
6. Zeng Y, Forbes KC, Wu Z, Moreno S, Piwnica-Worms H,
Enoch T (1998) Replication checkpoint requires phosphorylation
of the phosphatase Cdc25 by Cds1 or Chk1.
Nature, 395: 507-510.
108 Mechanisms of tumour development
phase cyclin) and for activating mutations
of CDK4 (one of the partners of cyclin D1)
in some cancers. Indeed, the high complexity
of cell cycle effectors provides an
Telomerase assays have not yet entered
routine clinical practice, but there is considerable
interest in their possible use for
cancer diagnosis and prognosis. For example,
telomerase assays of urine sediments
may be useful for diagnosis of urinary tract
cancer (Kinoshita H et al., J Natl Cancer
Inst, 89: 724-730, 1997), and telomerase
activity levels may be a predictor of outcome
in neuroblastoma (Hiyama E et al.,
Nature Medicine, 1: 249-255, 1995).
The catalytic subunit of human telomerase,
hTERT, was cloned in 1997 (Lingner J, Cech
TR, Curr Opin Genet Dev 8: 226-232, 1998). It
has subsequently been shown that genetic
manipulations of hTERT which result in inhibition
of telomerase activity in tumour cells
limit their proliferation and often result in cell
death. This raises the possibility that telomerase
inhibitors may be a very useful form of
therapy for many or most types of cancer.
However, in tumours with long telomeres, it
may take many cell divisions before telomerase
inhibitors exert an anti-tumour effect.
When such drugs are developed they will
therefore need to be carefully integrated with
other anticancer treatments.
7. Hainaut P, Hollstein M (2000) p53 and human cancer:
the first ten thousand mutations. Adv Cancer Res, 77: 81-
137.
8. Hartwell LH, Kastan MB (1994) Cell cycle control and
cancer. Science, 266: 1821-1828.
9. Kinzler KW, Vogelstein B (1997) Cancer-susceptibility
genes. Gatekeepers and caretakers. Nature, 386: 761, 763.
10. Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt
O, Reed SI (2001) Human F-box protein hCdc4 targets
cyclin E for proteolysis and is mutated in a breast cancer
cell line. Nature, 413: 316-322.
11. Schuuring E (1995) The involvement of the chromosome
11q13 region in human malignancies: cyclin D1 and
EMS1 are two new candidate oncogenes--a review. Gene,
159: 83-96.
extremely diverse range of possibilities for
cancer-associated alterations. In this
respect, cancer can be seen as, fundamentally,
a disease of the cell cycle.
Fig. 3.29 Telomeres contain repetitive DNA
sequences that cap the ends of chromosomes.
Quantitative fluorescence in situ hybridization
analysis of human metaphase chromosome
spreads is shown, using oligonucleotide probes
specific for telomere (white) and centromere (red)
DNA sequences, and the DNA dye DAPI (blue).
From the laboratory of Drs J.W. Shay and W.E.
Wright.
A potential challenge facing telomerase
research is the finding that some cancers
maintain their telomeres by a mechanism
that does not involve telomerase,
referred to as alternative lengthening of
telomeres, ALT (Bryan TM et al., Nature
Medicine, 3: 1271-1274, 1997; Reddel RR,
J Clin Invest, 108: 665-667, 2001).
WEBSITES
Animation of the phases of the cell cycle and of mitosis:
http://www.cellsalive.com/
Nature Reviews, “Focus on cell division”:
http://www.nature.com/ncb/celldivision/
The Forsburg laboratory home pages, a guide to the cell
cycle and DNA replication in S. pombe:
http://pingu.salk.edu/ ~ forsburg/lab.html